Nebulized Fentanyl in Patients With Mild to Moderate Idiopathic Pulmonary Fibrosis and Chronic Dyspnea

Study Description

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Brief Summary:

Patients with idiopathic pulmonary fibrosis (IPF) experience distressing activity-related respiratory discomfort which is challenging to manage therapeutically. Interventions such as pulmonary rehabilitation, collaborative self-management, supplemental oxygen therapy and oral opiate medications, are variably effective and therapeutic responses to each in individual patients are difficult to predict. The purpose of this study is to evaluate the acute effects of inhaled opiate therapy (fentanyl citrate) on breathing discomfort (dyspnea) in individuals with mild-to-moderate IPF, as well as examine the potential mechanisms of dyspnea relief.

Condition or disease	Intervention/treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Fentanyl Citrate; Drug: Placebo	Phase 3

Detailed Description:

Treatment with opioids can improve activity related dyspnea by reducing central respiratory neural drive. Inhaled fentanyl citrate is an opioid that is generally well tolerated and has been shown to effectively relieve respiratory discomfort without causing systemic side-effects, although its mechanism of action are poorly understood. Based on the current evidence, non-sedating, rapidly active inhaled fentanyl represents a possible alternative and effective treatment of severe dyspnea in patients with IPF who require urgent treatment. As such, the primary objective of this study is to examine the acute effects of nebulized fentanyl on dyspnea intensity and quality in patients with mild-to-moderate IPF, as well as examine the neurophysiological mechanisms of dyspnea relief during fentanyl inhalation. It is believed that fentanyl when compared with placebo, will reduce inspiratory neural drive to the diaphragm and breathing frequency, resulting in improvements in dyspnea intensity during physical exertion. Alternatively, dyspnea relief after inhaled fentanyl may be independent of changes in neural drive, and instead linked to the presence of opioid receptors in the lungs that modulate afferent inputs to the brain, thereby favourably influencing perceived dyspnea.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	20 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Double (Participant, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Use of Nebulized Fentanyl in Patients With Mild-to-Moderate Idiopathic Pulmonary Fibrosis and Chronic Dyspnea
Study Start Date :	January 2017
Estimated Primary Completion Date :	July 2018
Estimated Study Completion Date :	July 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Fentanyl Citrate; Single dose, nebulized 100 mcg fentanyl citrate. This is a double-blind, placebo-controlled, two-period crossover study comparing the effects of a single dose of nebulized 100 mcg fentanyl citrate to that of a placebo (0.9% saline). Treatments will be in randomized order: patients in one study arm will receive fentanyl at the first treatment visit and placebo at the second treatment visit, patients in the other arm will receive placebo first and fentanyl second.	Drug: Fentanyl Citrate; 100 mcg fentanyl citrate will be inhaled via nebulizer.; Other Name: inhaled fentanyl
Placebo Comparator: Placebo; Single dose, nebulized 0.9% saline solution. This is a double-blind, placebo-controlled, two-period crossover study comparing the effects of a single dose of nebulized 100 mcg fentanyl citrate to that of a placebo (0.9% saline). Treatments will be in randomized order: patients in one study arm will receive fentanyl at the first treatment visit and placebo at the second treatment visit, patients in the other arm will receive placebo first and fentanyl second.	Drug: Placebo; 0.9% saline solution will be inhaled via nebulizer; Other Name: normal saline

Outcome Measures

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Primary Outcome Measures :

1. Dyspnea intensity measured by the 10-point Borg Scale at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   The 10-point Borg scale ranges from 0 "nothing at all" to 10 "maximal/extremely strong" and will be used to rate the intensity of dyspnea during exercise: a decrease in this rating signifies an improvement. Dyspnea intensity will be assessed at a standardized time (4-minutes) in both post-treatment constant-load treadmill tests.

Secondary Outcome Measures :

1. Diaphragm electromyography (EMGdi) at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   EMGdi will be used as an index of inspiratory neural drive. Assessments will be compared at a standardized time (4-minutes) during both post-treatment constant-load treadmill tests.
2. Ventilation at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   Exercise measurements of minute ventilation will be compared at a standardized time (4-minutes) during both post-treatment constant-load treadmill tests.
3. Breathing frequency at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   Exercise measurements of breathing frequency (respiratory rate) will be compared at a standardized time (4-minutes) during both post-treatment constant-load treadmill tests.
4. Tidal volume at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   Exercise measurements of tidal volume will be compared at a standardized time (4-minutes) during both post-treatment constant-load treadmill tests.
5. Inspiratory capacity at a standardized time during treadmill exercise [ Time Frame: 10-minutes post-treatment ]
   Exercise measurements of inspiratory capacity will be compared at a standardized time (4-minutes) during both post-treatment constant-load treadmill tests.

Eligibility Criteria

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Ages Eligible for Study:	40 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• A total lung capacity (TLC) <lower limit of normal and ≥60%predicted, a forced vital capacity (FVC) <lower limit of normal and ≥60%predicted, and a forced expiratory volume in 1 second (FEV1)/FVC >70%.
• Clinically stable as defined by no changes in medication dosage or frequency of administration with no exacerbations or hospital admissions in the preceding 6 weeks.
• Moderate-to-severe chronic activity related dyspnea as defined by a Baseline Dyspnea Index total score ≤6.
• Ability to perform all study procedures and provide/sign informed consent.

Exclusion Criteria:

• Women of childbearing age who are pregnant or trying to become pregnant.
• Diffusing capacity of the lung for carbon monoxide (DLCO) <40 %predicted.
• Presence of active cardiopulmonary disease other than IPF that could contribute to dyspnea and exercise limitation.
• History of allergy or adverse response to fentanyl.
• Presence of important contraindications to clinical exercise testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s).
• Use of daytime oxygen or exercise-induced oxygen desaturation to < 80% on room air.
• Body mass index (BMI) <18.5 or ≥35.0 kg/m2.
• Use of antidepressant drugs (i.e., monoamine oxidase inhibitors, serotonin reuptake inhibitors) in the previous 2 weeks.
• Use of opioid drugs (e.g., morphine, fentanyl, oxycodone, codeine, etc.) in the previous 4 weeks.

Note: Healthy volunteers will only be used to assist in the characterization of the IPF study group, i.e., for comparison of baseline exercise responses. They will not undergo treatment.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Megha Ibrahim Masthan	613-549-6666 ext 4314	mim5@queensu.ca

Locations

Canada, Ontario
Respiratory Investigation Unit, Queen's University	Recruiting
Kingston, Ontario, Canada, K7L 2V7
Contact: Kathy Webb, M.Sc. 613-549-6666 ext 4950 kw2@queensu.ca
Principal Investigator: Denis E O'Donnell, MD, FRCPC

Sponsors and Collaborators

Queen's University

Boehringer Ingelheim (Canada) LTD

Investigators

Principal Investigator:	Denis E O'Donnell, MD, FRCPC	Queen's University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Dr. Denis O'Donnell, Principal Investigator, Queen's University
ClinicalTrials.gov Identifier:	NCT03018756 History of Changes
Other Study ID Numbers:	DMED-1921-16
First Posted:	January 12, 2017
Last Update Posted:	January 12, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Idiopathic Interstitial Pneumonias; Dyspnea; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Lung Diseases, Interstitial; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms; Fentanyl; Citric Acid; Analgesics, Opioid	Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anticoagulants; Calcium Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action